Telomeres are specialized capping structures on chromosomes that play important roles in aging, cancer and genome stability. With each cell division, telomeres progressively shorten such that upon reaching a critical stage, they signal cells to stop dividing. This process likely prevents cells from acquiring mutations that may result in cancer or aging. When mutations occur in crucial genes that regulate telomere maintenance or checkpoint responses (such as p53 and ATM), telomeres become critically shortened and dysfunctional. Our recent findings linking telomere dysfunction to precursor/stem cell depletion and accelerated aging in the combined telomerase Atm mutant mouse model provide a unique opportunity and genetic platform to explore the molecular mechanisms by which telomere dysfunction contributes to aging, organ homeostasis and tumorigenesis. We hypothesize that mice engineered to have critically short telomeres and defective checkpoint responses due to mTerc and Atm deficiency will be predisposed to either accelerated aging or tumorigenesis depending on p53 status. We also believe that reconstitution of telomerase activity in different organ compartments of these mice will, depending on the state of the genome at the time of the reconstitution, either strongly promote organ specific tumor progression or rescue the organ stem/progenitor cell depletion phenotype as well as suppressing tumorigenesis. Lastly, detailed molecular characterization of pathways leading to activation of p53 function in primary cells and tissues from these compound mutant mice with accelerated aging and precursor/stem cell depletion will dissect the molecular pathways that are involved in the process of aging and organ homeostasis.